Systematic review of oral cryotherapy for the management of oral mucositis in cancer patients and clinical practice guidelines.

PURPOSE: To update the 2013 Multinational Association of Supportive Care in Cancer/International Society of Oral Oncology (MASCC/ISOO) clinical practice guidelines on oral cryotherapy for the management of oral mucositis (OM) caused by cancer therapies. METHODS: A systematic review was conducted by the Mucositis Study Group of MASCC/ISOO. The evidence for each intervention for specific cancer treatment modalities was assigned a level of evidence (LoE). The findings were added to the database used to develop the 2013 MASCC/ISOO clinical practice guidelines. Based on the LoE, the guidelines were set as: recommendation, suggestion, or no guideline possible. RESULTS: A total of 114 papers were identified: 44 from PubMed and 70 from Web of Science. After abstract triage and merging with the 2013 database, 36 papers were reviewed. The LoE for prevention of OM with oral cryotherapy in patients undergoing autologous hematopoietic stem cell transplant using high-dose melphalan conditioning protocols was upgraded, and the guideline changed to recommendation. Additionally, the recommendation for prevention of OM with oral cryotherapy in patients receiving bolus 5-fluorouracil for the treatment of solid tumors was confirmed. No guidelines were possible for other clinical settings. CONCLUSIONS: The evidence supports recommendations for the use of oral cryotherapy for the prevention of OM for either (i) patients undergoing autologous hematopoietic stem cell transplant with high-dose melphalan conditioning protocols or (ii) patients receiving bolus 5-fluorouracil chemotherapy.

A single nucleotide polymorphism in SLC7A5 is associated with gastrointestinal toxicity after high-dose melphalan and autologous stem cell transplantation for multiple myeloma.

Multiple myeloma is the most frequent indication for high-dose melphalan (HDM) chemotherapy with autologous stem cell transplantation (ASCT). Gastrointestinal symptoms represent the most significant nonhematological toxicity of HDM. However, specific, especially genetic, predictors of their incidence or clinical severity are lacking. The amino acid transporters LAT1 and LAT2 encoded by the SLC7A5 and SLC7A8 genes, respectively, are the principal mediators of melphalan uptake into cells. To determine whether genetic variability at these loci contributed to interindividual differences in the development of gastrointestinal complications of HDM, we analyzed single nucleotide polymorphisms (SNPs) in these genes in 135 patients with multiple myeloma treated with HDM and ASCT and correlated these with the need for total parenteral nutrition (TPN). Seven SNPs in SLC7A5 and 20 in SLC7A8 were genotyped. Multiple analyses indicated that 1 SNP in the first intron of SLC7A5, rs4240803, was significantly associated with TPN use (odds ratio = .45, 95% confidence interval, .25 to .79; P = .007). Further, every haplotype that correlated with TPN requirement included this SNP. These results suggest that variability in melphalan transport affects mucosal injury after HDM. This finding could help in individualizing the dose of this effective and widely used chemotherapeutic agent for multiple myeloma.

Safety and efficacy of targeted-dose busulfan and bortezomib as a conditioning regimen for patients with relapsed multiple myeloma undergoing a second autologous blood progenitor cell transplantation.

Patients with multiple myeloma (MM) who relapse after autologous transplantation have limited therapeutic options. We conducted a prospective, multicenter, phase IIa study to investigate the safety and efficacy of i.v. busulfan (Bu) in combination with bortezomib as a conditioning regimen for a second autotransplantation. Because a safe Bu exposure was unknown in patients receiving this combination, Bu was initially targeted to a total area under the concentration-time curve (AUC) of 20,000 µM × minute. As no concentration-limiting toxicity was observed in 6 patients, this Bu exposure was utilized in the following treatment cohort (n = 24). Individualized Bu dose, based on test dose .8 mg/kg pharmacokinetics (PK), was administered daily for 4 consecutive days starting 5 days before transplantation, followed by a single dose of bortezomib (1.3 mg/m(2)) 1 day before transplantation. The total mean dose of i.v. Bu (including the test dose and 4-day administration) was 14.2 mg/kg (standard deviation = 2.48; range, 8.7 to 19.2). Confirmatory PK demonstrated that only 2 of 30 patients who underwent transplantation were dosed outside the Bu AUC target and dose adjustments were made for the last 2 doses of i.v. Bu. The median age was 59 years (range, 48 to 73). Median time from first to second transplantation was 28.0 months (range, 12 to 119). Of 26 evaluable patients, 10 patients attained a partial response (PR) or better at 3 months after transplantation, with 2 patients attaining a complete response. At 6 months after transplantation, 5 of 12 evaluable patients had maintained or improved their disease status. Median progression-free survival was 191 days, whereas median overall survival was not reached during the study period. The most common grade 3 and 4 toxicities were febrile neutropenia (50.0%) and stomatitis (43.3%). One transplantation-related death was observed. A combination of dose-targeted i.v. Bu and bortezomib induced PR or better in one third of patients with MM who underwent a second autotransplantation, with acceptable toxicity.

Hematopoietic progenitor cell transplantation toxicities in multiple myeloma patients with bisphosphonate-induced osteonecrosis of the jaw: a longitudinal cohort study.

PURPOSE: There is no information regarding the toxicity associated with autologous hematopoietic progenitor cell transplantation (AHPCT) in patients with multiple myeloma (MM) who have bisphosphonate-induced osteonecrosis of the jaw (ONJ). There is also limited information regarding long-term outcome of these patients. METHODS: In this retrospective cohort study, we compared the toxicity after AHPCT in MM patients with and without ONJ. We also analyzed the response rate and overall survival of this population of patients. RESULTS: During the study period, 176 patients underwent AHPCT at our institution for MM. Ten patients with ONJ prior to AHPCT were matched to 40 control patients without ONJ. The incidence and severity of transplantation-associated toxicities were similar in both groups, including mucositis, 50 % in patients with ONJ vs. 68 % in controls (p = 0.889) and febrile days, median 1 vs. 3 days, respectively (p = 0.524). Myeloid engraftment and hospital length of stay were also similar between patients with ONJ and controls. There were significantly more complete remissions in patients with ONJ than in control patients (45 % vs. 15 %, p = 0.0336), but survival between the groups was not significantly different (log-rank p = 0.0818). CONCLUSIONS: We conclude that the incidence and severity of transplantation-associated toxicities are similar in MM patients with and without ONJ. Long-term survival was also similar between both groups.

Loss of in vitro resistance in Candida glabrata following discontinuation of fluconazole prophylaxis in a hematopoietic stem cell transplantation patient.

We report a case of fluconazole-resistant oropharyngeal colonization caused by a strain of Candida glabrata that rapidly regained susceptibility once prophylaxis with this agent was discontinued and echinocandin therapy was initiated. Isolates collected before and after discontinuation of fluconazole were confirmed to be isogenic by RAPD analysis. Transcription analysis demonstrated constitutive expression of genes encoding efflux pumps in the isolate recovered on fluconazole prophylaxis and transient expression in those isolates collected after fluconazole was discontinued.

The department of veterans affairs nutritional status classification scheme allows for rapid assessment of nutritional status prior to autologous peripheral blood stem cell transplantation and identifies patients at high risk of transplant-related complications.

The nutritional assessment of patients prior to autologous peripheral blood stem cell transplantation (APBSCT) is labor intensive. A simple method of nutritional assessment prior to APSCT would be extremely helpful, especially if this method could identify patients at high risk of transplant-related complications. The Department of Veterans Affairs (VA) developed a Nutritional Status Classification Scheme (NSCS) to identify nutritionally compromised inpatients rapidly and reliably. The objective of this study was to determine if the use of the VA-NSCS could be utilized as a tool for the evaluation of patients prior to APBSCT and to determine if this tool could be used to identify patients at high risk of transplant-related complications. The nutritional status of 128 patients who underwent APBSCT was assessed by a registered dietician, utilizing the VA-NSCS, upon admission to the hospital and prior to conditioning regimen. Patients with moderately compromised nutritional status pretransplantation experienced a higher incidence of infections, longer duration of diarrhea, and longer length of hospital stay when compared to patients with normal or mildly compromised nutritional status. Our study demonstrates that the VA-NSCS, a simple and inexpensive tool to assess nutritional status, was useful in determining the pretransplant nutritional status of patients with lymphogenous malignancies who underwent APBSCT. In addition, this method was able to identify patients at a higher risk of posttransplant complications. Future studies should be undertaken to determine the optimal method for the nutritional assessment of autologous stem cell transplant candidates.

Methodological and logistical considerations to study design and data collection in racial/ethnic minority populations evaluating outcome disparity in hematopoietic cell transplantation.

Outcome disparity associated with race or ethnicity in the United States has been observed in hematopoietic cell transplantation (HCT). The underlying reasons for such disparity are not known. In the United States, an optimal study of health care disparity by race or ethnicity involves consideration of both biologic and psychosocial determinants, which requires an adequately powered, prospective cohort study design. To better characterize the nature and quantify the magnitude of the many impediments relevant to conducting a successful prospective study involving racial or ethnic minorities in HCT, we conducted a feasibility study to help guide planning of a larger scale outcome and disparity study in HCT. The primary questions to be addressed in the study were: (1) can we establish a racially or ethnically diverse patient sample that will respond to a survey focused on sociodemographic, economic, health insurance, cultural, spiritual, and religious well-being, and social support information? (2) What is the retention rate in the study over time? (3) What is the quality of the data collected from the patients over time? The challenges we faced in conducting this multicenter feasibility study are summarized in this report. Despite the difficulty in conducting disparity studies in racial and ethnic minorities, such studies are essential to ensure that people of all ethnic and racial backgrounds have the best chance possible of benefiting from HCT.

Microbiology and epidemiology of oral yeast colonization in hemopoietic progenitor cell transplant recipients.

OBJECTIVE: We monitored the epidemiology and microbiology of oral yeast colonization in patients undergoing hemopoietic progenitor cell transplantation (HPCT) to examine associations between yeast colonization and oral mucositis. STUDY DESIGN: One hundred twenty-one consecutive HPCT patients were sampled for oral yeasts prior to fluconazole (FLC) prophylaxis, at transplantation, and weekly until discharge. Clinical oral mucositis screenings were performed triweekly. RESULTS: Yeast colonization was evident at 216 of 510 total visits. Candida albicans and Candida glabrata were the predominant organisms. Eight patients showed elevated minimal inhibitory concentrations to FLC. One patient developed fungal septicemia. Patients with oral mucositis assessment scale scores <20 had higher colonization rates than those with higher scores. CONCLUSIONS: FLC is effective in controlling a variety of oral yeasts in HPCT recipients. FLC-resistant yeasts do emerge and can be the source of fungal sepsis. A positive association was not shown between yeast colonization and the presence or severity of oral mucositis.

Toxicity of a second autologous peripheral blood stem cell transplant in patients with relapsed or recurrent multiple myeloma.

Toxicity associated with a second autologous peripheral blood stem cell transplant (APBSCT) in patients who relapse following initial APBSCT for multiple myeloma (MM) has not been well described. We conducted a retrospective, case-series of 25 consecutive patients who received a second APBSCT for relapsed or progressive disease following prior APBSCT to describe associated toxicity. Grade 3 or 4 toxicities were observed in 92% of patients after each APBSCT. More patients developed an elevated serum creatinine (4%vs. 36%; p = 0.011) following the second APBSCT. Median time to neutrophil engraftment was 10 days following both transplants (p = 0.428). Platelet engraftment was delayed by 2 days after the second APBSCT (median 12 vs.14 days; p < 0.025). There were two deaths before day 100. In conclusion, patients who undergo a second APBSCT for relapsed MM experience more nephrotoxicity. Delayed platelet engraftment and an 8% treatment-related mortality were observed following the second APBSCT.

Patterns of use of vascular access devices in patients undergoing hematopoietic stem cell transplantation: results of an international survey.

INTRODUCTION: There is limited information regarding of use of vascular access devices (VAD) in patients undergoing hematopoietic stem cell transplantation (HSCT). The frequent use of VAD in HSCT and its potential to cause morbidity requires understanding of the general use of VAD in HSCT. MATERIALS AND METHODS: A World Wide Web-based 19-item questionnaire was designed to determine the patterns of use of VAD in patients undergoing HSCT. The questionnaire was sent via electronic mail to the directors of HSCT programs throughout the world. RESULTS: Of the 445 centers surveyed, 163 centers replied for a response rate of 37%. The most commonly used catheter for autologous peripheral blood stem cell (PBSC) harvest is the dual-lumen plasmapheresis/hemodialysis (62%). Of the institutions, 58% utilize the same catheter used for PBSC harvest to provide vascular access support during the transplant. Catheter-related blood stream infection (36%) and withdrawal occlusion (31%) were the most frequently encountered complications of VAD. Of the centers, 65% have established criteria for VAD removal when infection is suspected and 48% when occlusion is suspected. DISCUSSION: Our study demonstrated that there are similarities in the utilization of VAD but also wide differences in the standard procedures for the insertion and care of VAD in the transplant setting. More comprehensive studies are needed to assess the use of central venous catheters in transplant recipients. Important areas for future research include the impact of VAD utilization on the quality of life of transplant recipients and the final consequences of VAD complications.

Candida krusei sepsis secondary to oral colonization in a hemopoietic stem cell transplant recipient.

Yeasts other than Candida albicans have emerged as important causes of fungal infection in hemopoietic stem cell transplant (HSCT) patients, particularly those receiving fluconazole prophylaxis. We report on an autologous hemopoietic stem cell transplant recipient who developed Candida krusei sepsis from pre-existing oral colonization.

Loss of calcineurin Aalpha results in altered trafficking of AQP2 and in nephrogenic diabetes insipidus.

The serine/threonine phosphatase calcineurin is an important signaling molecule involved in kidney development and function. One potential target of calcineurin action is the water channel aquaporin 2 (AQP2). In this study, we examined the effect of loss of calcineurin Aalpha (CnAalpha) on AQP2 function in vivo. CnAalpha null mice were found to have defective post-natal urine-concentrating ability and an impaired urine-concentrating response to vasopressin. Expression of AQP2 is normal but, paradoxically, vasopressin-mediated phosphorylation of the channel is decreased compared with wild-type littermates and there is no accumulation of AQP2 in the apical membrane. Calcineurin protein and activity was found in innermedullary collecting duct vesicles, and loss of calcineurin expression and activity was associated with a loss of AQP2 in the vesicle fraction. As such, the lack of vasopressin-mediated phosphorylation of AQP2 might be the result of a defect in normal trafficking of AQP2 to apical-targeted vesicles. Likewise, treatment of wild-type mice with cyclosporin A to inhibit calcineurin produces a similarly impaired urine-concentrating response to vasopressin and alterations in AQP2 phosphorylation and trafficking. These experiments demonstrate that, CnAalpha is required for normal intracellular trafficking of AQP2 and loss of calcineurin protein or activity disrupts AQP2 function.

Calcineurin A-alpha but not A-beta is required for normal kidney development and function.

Calcineurin is an important signaling molecule in the kidney and may be involved in a variety of processes. The phosphatase subunit of calcineurin (CnA) has three isoforms, alpha, beta, and gamma. In this study, we investigated the effect of loss of calcineurin A-alpha (CnA-alpha) or calcineurin A-beta (CnA-beta) on the development and function of the kidney. Total calcineurin expression and activity was significantly reduced in whole kidney homogenates from both CnA-alpha -/- and CnA-beta -/- mice. Kidneys of CnA-beta -/- mice appear normal and the mice develop with no phenotypic abnormalities. In contrast, kidneys of CnA-alpha -/- animals fail to fully develop. In particular, postnatal maturation of the nephrogenic zone (NZ) is defective. Within the NZ, glomeruli also fail to mature and lack mesangial cells. In addition to alterations in development, there is an absence of proliferation and an increase of cell death in the NZ with loss of CnA-alpha. Finally, increased collagen deposition is observed and serum creatinine levels are significantly increased in CnA-alpha -/- animals compared to wild-type littermates, indicating that kidney function is impaired. In summary, absence of CnA-alpha but not CnA-beta leads to a defect in normal maturation of the NZ and glomeruli, alterations in the cell cycle, and impaired kidney function.